Rapid miosis with control of intraocular pressure

ABSTRACT

Quick miosis with 24 hour control of intraocular pressure of patients undergoing extracapsular cataract extraction surgery is achieved by applying to the eyes of the patient during surgery acetylcholine as a first miotic agent and carbachol as a second miotic agent. Acetylcholine provides quick miosis while carbachol enhances the miotic effect while providing post-surgery control of intraocular pressure. The two miotic agents can be dissolved in a common saline carrier. The two agents can be combined in a unit dosage package by disposing acetylcholine in powder form in a first compartment and a solution of carbachol in a second compartment. The combined miotic agent of the invention is especially useful when substances which raise IOP such as viscoelastic agents are used during ocular surgery and/or with sensitive patients who enter the surgery with elevated pressure such as those suffering from glaucoma.

TECHNICAL FIELD

This invention relates to a miotic agent useful in post-operativecataract and intraocular lens surgery and, more particularly, to acombination of miotic agents that provides quick miosis with control ofintraocular pressure 24 hours after surgery.

BACKGROUND OF THE INVENTION

Miotic agents are frequently used by ophthalmologic surgeons duringintraocular surgery. The anterior chamber is irrigated with a mioticagent after delivery of the lens in cataract surgery as well as inpenetrating keratoplasty, iridectomy and other anterior segment surgery.Prompt miosis is necessary to ensure that a round pupil is obtainedafter cataract surgery. If any of the iris of the eye is caught in theincision or if a capsular tag is caught in the incision, the pupil willbe distorted on the following day. It is easy to miss a capsular tag inthe incision since the tag is clear and transparent unless one uses amiotic agent. The other advantages obtained by the use of miotics arethe facilitation of post-placed corneal scleral sutures, anteriorchamber lens insertion and a decrease in post-operative peripheralanterior synechias. Many surgeons feel that miotic agents help incentering and positioning the intraocular lens implant.

Elevated intraocular pressure (IOP) can interfere with normalfunctioning and may result in irreversible loss of visual function.Viscoelastic agents such as Healon are often used during lensimplantation which can cause elevated IOP with pressure spiking.

With the advent of modern surgical techniques and the trend to "in thebag" placement of posterior chamber IOL's, more and more viscoelasticsubstances are being used. Increasingly, cataract surgery is being doneon an out-patient basis, and the patient returns to the physician'soffice the following day. Slit lamps and applanation tonometry arehandy, and consequently most surgeons are examining their post-operativepatients even better than when they were hospitalized. This has improvedpatient care and, on the other hand, has perhaps resulted in increasedawareness of the IOP 20-24 hours after cataract surgery.

Pressure studies have shown that the IOP in the first 24 hours aftercataract surgery may be very important. Damage by raising IOP ispossible to the optic nerve, the vascular supply within the eye, and thecorneal endothelium (15) (7). Consequently, every effort should be madeto control the IOP from the very onset of the post-operative period.

Acetylcholine (Miochol) is the most popular miotic agent utilized byophthalmologic surgeons. Miochol provides quick miosis (within minutes).However, it provides very poor control of IOP after several hours, evenwhen pressure control agents such as acetazolamide (Diamox) areutilized. Carbachol (Miostat) does not provide as quick a miosis and isnot as widely used. A miotic agent providing quick miosis with controlof intraocular pressure 24 hours after surgery is needed.

DESCRIPTION OF THE PRIOR ART

Gormaz (3), in 1962, first reported increases in IOP in the immediateperiod after cataract extractions. Rich (4) (5) in 1968 and 1969 found asignificant rise in IOP was characteristic after cataract surgery. Healso showed that α-chymotrypsin was not required to produce thisincrease. Sodium hyaluronate (Healon) has been implicated as causing arise in IOP. Olivius and Thornburn (6) have shown that sodiumhyaluronate induced increased IOP, and is partially reversible byremoval or dilution of the viscoelastic material by irrigation (7).

Several drugs have been used to counteract the increase in IOPassociated with cataract surgery. Rich (3) in 1969 demonstrated alowering of IOP 24 hours after surgery with the use of acetazolamide(Diamox) in high doses during the 24 hours following cataract surgery.However, acetazolamide has some undesirable side effects in somepatients. Although Timolol effectively lowered IOP after ICCE (8), itwas found to have no effect in acute post-operative pressure elevationsfollowing ECCE with IOL and the use of sodium hyaluronate (9). Recently,a simple administration of pilocarpine gel was found to be effective inreducing IOP for the first 24 hours after ECCE with IOL (10). However,patients frequently complained of brow ache the next day. This samegroup, however, felt that there was a trend in lowering IOPpost-operatively using Timolol.

Miotic agents came into use in about 1970, shortly after the onset ofECCE. In 1972, Beasley (11) found that miosis was rapid with bothacetylcholine 1% and Carbachol 0.01%. With Carbachol, miosis extendedinto the first post-operative day, unlike acetylcholine, where themiotic effect is gone within a very short time. However, Holland, Dranceand Schulzer (13), showed that acetylcholine 1% has a more rapid onsetof miosis than does Carbachol 0.01%. Holland, Drance and Schulzer (14)showed that acetylcholine 1%, administered intracamerally duringcataract surgery, significantly reduced the IOP at 3 and 6 hourspost-operatively but had no effect beyond this time. On the other hand,this same group of investigators showed that Carbachol 0.01% was highlyeffective in reducing IOP for at least 24 hours post-operatively, and inreducing the number of patients developing IOP greater than 30 mm.Hg.

List of Cited References BIBLIOGRAPHY

(1) U.S. Pat. No. 4,459,309

(2) U.S. Pat. No. 4,665,094

(3) Gormaz, A.: Ocular Tension After Cataract Surgery. American Journalof Ophthalmology, 43:832, 1962.

(4) Rich, W. J. C. C.: Intraocular Pressures and Wound Closure AfterCataract Extraction. Trans. Ophthalmol. Soc., U.K. 88:437, 1968.

(5) Rich, W. J. C. C.: Further Studies on Early Post-operative OcularHypertension Following Cataract Extraction. Trans. Ophthalmol. Soc.,U.K. 89:639, 1969.

(6) Olivius, E., and Thornburn, W.: Intraocular Pressure After Surgerywith Healon. Am. Intraocular Implant Soc. J. 11:480, 1985.

(7) Chergan, G. M., Rich, W. J. and Wright, G.: Raised IntraocularPressure and Other Problems with Sodium Hyaluronate and CataractSurgery. Trans. Ophthalmol. Soc., U.K. 103:277, 1983.

(8) Obstbaum, S. A. and Galin, M. A.: The Effects of Timolol on CataractExtraction and Intraocular Pressure. Am. J. Ophthalmol. 88:1017, 1979.

(9) Tomoda, T., Tuberville, A. W., and Ward, T. O.: Timolol andPostoperative Intraocular Pressure. Am. Intraocul. Implant Soc. J.,10:180, 1984.

(10) Ruiz, R. S., Wilson, C. A., Musgrove, K. H. and Prager, T. C.:Management of Increased Intraocular Pressure After Cataract Extraction.Am. J. Ophthalmol., 103:487, 1987.

(11) Beasley, H.: Miotics In Cataract Surgery. Arch. Ophthalmol., 88:49,1972.

(12) Douglas, G. R.: A Comparison of Acetylcholine and CarbacholFollowing Cataract Extraction. Can. J. Ophthalmol., 8:75, 1973.

(13) Holland, R. H., Drance, S. M., and Schulzer, M.: The Effect ofIntracamerol Carbachol on Intraocular Pressure After CataractExtraction. Am. J. Ophthalmol., 104:225, 1987.

(14) Hollands, R. H., Drance, S. M., and Schulzer, M.: The Effect ofAcetylcholine on Early Postoperative Intraocular Pressure. Am. J.Ophthalmol., 103:749, 1987.

(15) Hayrch, S. S.: Anterior Ischemic Optic Neuropathy, IV, OccurrenceAfter Cataract Extraction. Arch. Ophthalmol., 98:1410, 1980.

STATEMENT OF THE INVENTION

An improved miotic agent is provided in accordance with this inventionthat provides rapid miosis with 24 hour control of intraocular pressure.The miotic agent of the invention reduces or eliminates the need for IOPcontrol agents such as Diamox and reduces IOP after use of viscoelasticagents such as Healon.

The miotic agent of the invention resides in the combined use of anacetylcholine type of agent with a carbachol type of agent. Thecombination provides fast onset of miosis, a prolonged miotic effect,and long-term control of IOP for 24 hours. The IOP is maintained at orbelow 25 mmHg with very few, if any, pressure spikes in the 24 hour,post-operative period.

The miotic agent of the invention is convenient to use. The agent issafe and effective since it is a combination of two agents approved foruse in the same procedure. The miotic agent of the invention will findgeneral use in intraocular surgery and is especially useful in the classof patients who enter the procedure with elevated intraocular pressure,such as glaucoma patients. It will also prove very useful in proceduresin which Healon is used to aid in the insertion of an intraocular lens.

The acetylcholine and carbachol materials can be used sequentially orsimultaneously. Another aspect of the invention resides in packing thetwo agents in a common container having two separate compartments. Theagents are combined and dissolved in a common carrier immediately beforeuse.

These and many other features and attendant advantages of the inventionwill become apparent as the invention becomes better understood byreference to the following detailed description when considered inconjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a is an enlarged view of a package containing the component of themiotic agent of the invention;

FIG. 1b is a view taken along line 1b--1b of FIG. 1a;

FIG. 1c is a view similar to FIG. 1b but showing unit dosage and aqueoussolution mixed and ready to be withdrawn by a hypodermic needle.

FIG. 2 is a set of curves showing pre-operative and post-operativeintraocular pressure IOP in a group of patients receiving Miochol withDiamox;

FIG. 3 is a set of curves showing pre-operative and post-operativeintraocular pressure IOP in a group of patients receiving Miocholwithout Diamox;

FIG. 4 is a set of curves showing pre-operative and post-operativeintraocular pressure IOP in a group of patients receiving Miostat withDiamox;

FIG. 5 is a set of curves showing pre-operative and post-operativeintraocular pressure IOP in a group of patients receiving Miostatwithout Diamox;

FIG. 6 is a set of curves showing pre-operative and post-operativeintraocular pressure IOP in a group of glaucoma patients receivingMiochol;

FIG. 7 is a set of curves showing pre-operative and post-operativeintraocular pressure IOP in a group of glaucoma patients receivingMiostat; and

FIG. 8 is a series of bar graphs illustrating the pre- andpost-operative IOP in 18 patients administered the combined miotic agentof the invention.

DETAILED DESCRIPTION OF THE INVENTION

The first active agent in the miotic composition of the invention is acompound of the formula: ##STR1## where R and R¹ are lower alkyl groupscontaining 1 to 5 carbon atoms and X⁻ is an anion such as halo.

The preferred member of this group is acetylcholine where R and R¹ areall methyl and X⁻ is chloro. Acetylcholine is a parasympathemetic agent.It is utilized in concentrations from 0.1 to 5% usually at 1% by weight.Acetylcholine is unstable so it is provided in dry powder form and ismixed with physiologically inert, liquid carrier before use. The drymaterial can be mixed with an inert lyophizing material such as mannitolin ratios of 1/1 to 10/1, usually 3/1 by weight. The reconstitutedaqueous solution contains 1% acetylcholine and 3% mannitol by weight.The usual dose for administration is about 2 ml.

The second active material in the miotic composition is a compound ofthe formula: ##STR2## where R² is a low alkyl group of 1-5 carbon atoms,n is an integer from 0-3 and X is an anion such as halo. The preferredmaterial carbachol, is a compound in which n is 0, R² are all methyl andX is chloro. Carbachol is provided as a sterile aqueous salt solution ina concentration from 0.001 to 1.0 percent by weight, usually at about0.01% by weight. The isotonic salt carrier includes the followinginactive salts:

    ______________________________________                                        Salt             % by Weight                                                  ______________________________________                                        NaCl             0.64                                                         KCl              0.075                                                        CaCl.sub.2 · H.sub.2 O                                                                0.048                                                        MgCl.sub.2 · 6H.sub.2 O                                                               0.03                                                         Sodium acetate · 3H.sub.2 O                                                           0.39                                                         Sodium citrate · 2H.sub.2 O                                                           0.17                                                         ______________________________________                                    

The pH is adjusted to neutral with sodium hydroxide or hydrochloric acidas needed.

Referring now to FIG. 1, the two agents can be provided in a twocompartment package 10. The package is in the form of a uni-vial 12having a first compartment 14 sealed by a first elastomer plug 16 and asecond compartment 17 sealed by a second elastomer plunger-stopper 18.The first compartment 14 contains a unit dosage or charge 20 of thefirst agent such as acetylcholine and the lyophizing agent such amannitol and the second compartment 17 contains an aqueous solution 22of the second agent in a solution of salt in isotonic proportions andconcentrations. The plunger-stopper 16 is pressed downwardly whichforces the plug 18 into the lower compartment. The plunger-stopper 16comes to rest on the shoulder 25 formed along the rim 27 of the annularsection 31 of the uni-vial 10. The solution 22 falls into the firstcompartment 14 and dissolves the dry charge 20. In use, a hypodermicneedle, not shown, is inserted through the plunger-stopper 16 into thesecond compartment 17 to withdraw the solution. After the dry mixture ofcompounds is dissolved, the combined miotic agent is withdrawn into thesyringe and is ready for use.

Studies were conducted using Miochol (Acetylcholine) and Miostatsequentially, and combined separately during intraocular surgicalprocedures.

The miotic agent of the invention can be used as follows. Afterextraction of a cataract, the capsule is retained. It has an anteriorflap. To facilitate insertion of the lens, the capsule is inflated andHealon is applied. After insertion of the lens in the capsule, theMiochol agent is injected. As the pupil is constricting, closure of thewound takes place. The viscoelastic agent is removed from the capsulecoating by aspiration with saline. The Miostat solution is then added tothe anterior chamber. As the last stitching of the incision iscompleted, the iris is examined for roundness and for inclusion of irisor capsular tags in the incision.

When the combination of acetylcholine and carbachol is utilized in acommon carrier, a portion of the combination solution is added afterlens insertion and closure of the wound takes place. The viscoelasticagent is aspirated from the anterior chamber and the combination mioticagent is added again as the stitching of the wound is completed.

The following studies provide indications of the ability of thecombination miotic agent of the invention to provide long-term IOPcontrol without the use of Diamox and excellent control of glaucomapatients undergoing ECCE.

The average intraocular dose of Miochol is 0.5 to 2 ml of the 1%solution and of the Carbachol during surgery is 0.5 to 2 ml of a 0.01%solution.

The intraocular pressure was measured with the Goldman applanationtonometer the day before surgery during the pre-operative visit. Thesecond intraocular pressure measurement was taken 20-24 hours aftersurgery at the first post-operative visit.

SURGICAL TECHNIQUE

1. Standard ECCE with intraocular lens implantation (either PMMA withProlene loops, or all PMMA) was performed. All phakoemulsification withintraocular lens implantation patients were excluded. All known glaucomapatients were also excluded from this part of the study.

2. Methods and procedures: (a) Honam cuff 15-30 minutes pre-operatively,(b) approximately 11 mm incision, (c) manual extracapsular cataractextraction (pressure below, counter-pressure above), (d) Healon (sodiumhyaluronate) was used in all cases, (e) machine cortical irrigation andaspiration containing Epinephrine with either Site unit or Series 10,000Coopervision unit, (f) "in the bag" placement of the posterior chamberintraocular lens, (g) machine irrigation and aspiration of Healon, (h)Miotic agent instilled into the anterior chamber and the chamber wasaspirated to remove the Healon, (i) closure with interrupted 10-0 nylonsutures.

Injectable medication used at surgery were Garamycin (1/2 to 1 cc), andCelestone (1/2 to 1 cc).

3. Topical medications used upon completion of surgery were Tobrex,Maxidex, and Betoptic. Celestone, Maxidex and Betoptic are underlinedbecause they are known to affect intraocular pressure.

ECCE surgery has been conducted utilizing acetylcholine and carbacholsequentially and combined on two sets of patients. All surgeries weresuccessful with quick miosis followed by rapid lowering the IOP and lowIOP after 24 hours.

The following table and FIG. 8 show the IOP of 9 patients administeredthe two miotic agents sequentially. Quick miosis was observed. ThePost-Op IOP (24 hours after surgery) was the same or lower than thePre-Op pressure.

                  TABLE 1                                                         ______________________________________                                        Patient Pre-Op       Post-Op  Delta IOP                                       ______________________________________                                        1       15           15       0                                               2       15           16       1                                               3       12            7       -5                                              4       19           20       1                                               5       18           13       -5                                              6       21           16       -5                                              7       16           10       -6                                              8       19           16       -3                                              9       18           16       -2                                              ______________________________________                                    

The combined miotic agent of the invention was administered to 18additional subjects. Measurements of IOP were taken on the operated eye(OP) and the fellow (FEL) eye before the operation at surgery (PRE) and24 hours after the operation (POST). The pupil size was measured atsurgery (AT) and 24 hours after surgery (POST). The following Tableshows the measurements, the differences (DELTA) and the maximum, minimumand averages of the measurements.

                                      TABLE 2                                     __________________________________________________________________________                           Pupil                                                                            Pupil                                                                             Delta                                                                              Delta                                      Patient                                                                           Pre-Op                                                                            Pre-Fel                                                                            Post-Op                                                                            Post-Fel                                                                           AT POST                                                                              OP   FEL                                        __________________________________________________________________________     1  14  14   13   11   4.5                                                                              2    -1  -3                                          2  22  23   12   26   4  4   -10   3                                          3  18  18   20   15   5  1.5   2  -3                                          4  19  19    4   15   4  2.5 -15  -4                                          5  21  18   25   18   4  1.5   4   0                                          6  19  18   18   18   3  2    -1   0                                          7  20  20   21   17   3  2     1  -3                                          8  16  17   16   14   3.5                                                                              2     0  -3                                          9  18  17   18   12   2.5                                                                              2.5   0  -5                                         10  16  16    4   16   4  2   -12   0                                         11  18  21    5   20   4  2   -13  -1                                         12  16  16   18   18   4  2     2   2                                         13  13  14   16   16   6  3      3  2                                         14  18  20   18   26   3.5                                                                              2     0   6                                         15  16  16   16   15   4  2.5   0- -1                                         16  18  19   15   18   3  2    -3  -1                                         17  14  15   18   18   3.5                                                                              2     4   3                                         18  15  15   12   10   3  2    -3  -5                                         Max.                                                                              22  23   25   26   6  4     4   6                                         Min.                                                                              13  14    4   10   2.5                                                                              1.5 -15  -5                                         Ave.                                                                              17.278                                                                            17.5556                                                                            14.944                                                                             16.8333                                                                            3.81                                                                             2.194                                                                              -2.333                                                                            -0.72222                                   STD  2.4688                                                                            2.47867                                                                            5.8054                                                                             4.25994                                                                           0.82                                                                             0.572                                                                               5.9902                                                                            3.0444871                                 __________________________________________________________________________

The Post-Op IOP is lower than the Pre-Op IOP showing good control. Thepupil is still constricted 24 hours later.

A retrospective, clinical study was conducted on pre-operative andpost-operative intraocular pressures of patients administeredAcetylcholine or Carbachol while undergoing extracapsular, cataractextraction with intraocular lens implantation. The surgery was performedin a similar fashion by one surgeon (the author). Intraocular pressurewas measured with the Goldman applanation tonometer the day beforesurgery during the pre-operative visit. The second intraocular pressuremeasurement was taken by Goldman applanation tonometer 20-24 hoursfollowing surgery at the first post-operative visit.

In the early stages of this retrospective study, it became apparent thatpost-operative pressure spikes occurring 20-24 hours later were of amajor concern. This retrospective study compares the post-operativeintraocular pressure (IOP) in 4 groups following standard extracapsularcataract extraction with intraocular lens (ECCE with IOL). The 4 groupsconsisted of Miochol (acetylcholine chloride) alone, Miochol with 500mg. Diamox (acetazolamide) given orally at 1800 hours, Miostat(Carbachol) with 500 mg. Diamox given orally at 1800 hours, andfourthly, Miostat alone. FIGS. 2 and 3 show with Miochol with or withoutDiamox. FIGS. 4 and 5 show that the patients treated with Miostat withor without Diamox had good control of IOP. Surprisingly, the group notreceiving Diamox had better control.

The patients given Miochol only had an average pre-operative intraocularpressure of 14.2 and an average post-operative pressure of 26.5.However, 4 of these 11 patients had pressure spikes of over 30, and 1 of44 mmHg. The average increase in intraocular pressure was 12.3 mmHG.

35 patients were given Miochol at the time of surgery with 500 mg. ofDiamox orally at 1800 hours on the day of surgery, in an attempt toreduce pressure spikes. The average post-operative pressure was 20.1with an average increase of 6.8 mmHg. of pressure. However, in thisgroup, there were 9 of 35 patients with intraocular pressure of above 25to a high as 42.

38 patients were given Miostat at the time of surgery with Diamox 500mg. at 1800 hours the day of surgery. The average post-operativeintraocular pressure was 16.9, and the average increase in intraocularpressure was 2.3 mm. Only 3 of 38 patients had pressures over 25, thehighest being 29. This appeared to be an improvement in control ofintraocular pressure 20-24 hours later over both groups of patientsusing Miochol.

36 patients received only Miostat at surgery with no Diamox given theday of surgery. The average post-operative intraocular pressure wasreduced 0.8 mm. Only 1 of 36 patients had a post-operative intraocularpressure of over 25. This group appeared to be clinically at least aswell controlled as the Miostat with Diamox group, and certainlysuperiorly controlled to the Miochol group.

During this retrospective study, 16 known cases of glaucoma wereuncovered--an admittedly small group. All glaucoma cases were onmedication and felt to be controlled, although 2 patients, 1 in eachgroup, did have a pre-operative pressure of 25. 8 of these patients hadbeen given Miochol at surgery, and 8 had been given Miostat. All ofthese patients received Diamox 500 mg. at 1800 hours the day of surgery.(a) The surgical technique was the same except a full iridectomy wasperformed when indicted. (b) Injectable medications at the time ofsurgery were Garamycin and Celestone. (c) Topical medications used uponcompletion at surgery were Tobrex, Maxidex, and Betoptic. 500 mg. ofDiamox was used orally at 1800 hours the day of surgery in all cases.

FIG. 6 shows the data for the 8 patients who had been given Miochol atsurgery. The average pre-operative intraocular pressure was 21, and theaverage post-operative intraocular pressure was 37, an increase of 16.3mm. 7 of the 8 patients had intraocular pressures of 30 or over, onepatient's pressure spiked to 54 mm.

FIG. 7 shows the data for the 8 patients who had been given Miostat atsurgery. Average pre-operative intraocular pressure was 17, and theaverage post-operative intraocular pressure was the same. Only 2patients had intraocular pressures above 21, one patient of 26 and onepatient of 28. A comparison of the post-operative intraocular pressuresin the glaucoma population indicates that there was significant spikingof intraocular pressure 20-24 hours later in the Miochol group comparedto the Miostat group of patients.

This retrospective, clinical study of the use of standard ECCE supportsthe safety and efficacy of the combined miotic agent of the invention.The miotic agent containing both Miochol and Miostat (carbachol 0.01%)appears to be a superior pharmacological agent to one containing Miochol(acetylcholine chloride 1%) in controlling IOP 20-24 hours later, asmeasured by applanation tonometry. In the routine care of standard ECCEwith IOL, Diamox 500 mg. orally at 1800 hours does not seem necessary,if using the miotic agent of the invention containing both Miochol andMiostat. In glaucoma cases, the miotic agent of the invention should beeffective in providing quick miosis while controlling post-operative IOP20-24 hours later.

It is to be realized that only preferred embodiments of the inventionhave been described and that numerous substitutions, modifications andalterations are permissible without departing from the spirit and scopeof the invention as defined in the following claims.

I claim:
 1. A method of inducing quick miosis while controllingintraocular pressure in a mammal during ocular surgery comprising thesteps of:applying to the eye of the mammal during ocular surgery anaqueous solution containing from 0.1 to 5% by weight of a first mioticagent dissolved in a pharmacologically acceptable aqueous carrier, saidfirst agent being selected from compounds of the formula: ##STR3## whereR and R¹ are lower alkyl groups containing 1 to 5 carbon atoms and X⁻ isan anion; and applying to the eye during said surgery an aqueous salinesolution containing 0.001 to 1.0 percent by weight of a second mioticagent dissolved in pharmacologically acceptable aqueous carrier selectedfrom compounds of the formula: ##STR4## where R² is a lower alkyl groupof 1-5 carbon atoms, n is an integer from 0-3 and X is an anion.
 2. Amethod according to claim 1 in which R and R¹ are methyl and X⁻ ischloro.
 3. A method according to claim 2 in which R² is methyl, n is Oand X is chloro.
 4. A method according to claim 3 in which the twoagents are applied to the eye sequentially.
 5. A method according toclaim 4 in which the first agent is applied to the eye before the secondagent.
 6. A method according to claim 3 in which the two agents areapplied to the eye simultaneously.
 7. A method according to claim 1 inwhich X⁻ is a halogen anion.
 8. A method according to claim 1 in whichthe solution of first agent further includes a lyophilizing material ina weight ratio to agent of 1/1 to 10/1.
 9. A method according to claim 8in which the lyophilizing material is mannitol present in an amount ofabout 3% by weight.
 10. A method according to claim 8 in which thelyophilizing agent is mannitol.
 11. A method according to claim 1 inwhich the second agent is present in the saline solution in an amount ofabout 0.01% by weight.
 12. A method according to claim 11 in which bothmiotic agents are dissolved in the pharmacologically acceptable aqueoussaline as a common carrier.
 13. A method according to claim 12 in whichbefore applying the agents, the first agent is a dry powder and thelyophilizing agent is a dry powder in unit dosage form are disposed in afirst sterile, closed package and a unit dosage of the second agentdissolved in said saline is disposed in a second sterile package andfurther including the steps of:combining the contents of the twopackages to form a solution of the two agents in said saline and thenapplying said solution to the eye of said mammal.
 14. A method accordingto claim 1 in which the mammal is a human.
 15. A method according toclaim 14 in which the human subject is undergoing extracapsular cataractextraction with the intraocular lens implant surgery.
 16. A methodaccording to claim 15 in which the human subject is suffering fromglaucoma.
 17. A unit dosage package of a combination miotic capable ofquick miosis while controlling intraocular pressure comprising:a firststerile container containing a unit dosage of an aqueous saline solutioncomprising 0.001 to 1.0 percent by weight of a first miotic agent of theformula ##STR5## where R² is a lower alkyl group of 1-5 carbon atoms, nis an integer from 0-3 and X is an anion; a second sterile containercontaining a unit dosage in dry powder form of a second miotic agentselected from compounds of the formula: ##STR6## where R and R¹ arelower alkyl groups of 1-5 carbon atoms and X⁻ is an anion; said secondagent forming a solution having a concentration of 0.1 to 5 percent byweight when dissolved in said aqueous saline solution.
 18. A packageaccording to claim 17 in which the containers are joined by an elastomerseal penetrable by a hypodermic needle.
 19. A package according to claim17 in which R and R¹ are methyl and X⁻ is chloro.
 20. A packageaccording to claim 17 in which R² is methyl, n is O and X⁻ is chloro.21. A package according to claim 17 in which the containers arephysically joined.
 22. A method according to claim 1 in which the agentsare applied to the eye by injection.